Hepatobiliary Cysteinyl Leukotriene Elimination

Abstract

The cysteinyl leukotrienes, LTC₄, LTD₄, LTE₄, and N-acetyl-LTE₄, are highly potent lipid mediators which are derived from arachidonate (Lewis and Austen, 1984; Hammarström et al., 1985; Piper and Samhoun, 1987; Samuelsson et al., 1987). 5-Lipoxygenase/LTA₄ synthase (Dixon et al., 1988; Matsumoto et al., 1988) converts arachidonate to the epoxide LTA₄ which is subsequently conjugated with glutathione by a particulate LTC₄ synthase (Söderström et al., 1988; Yoshimoto et al., 1988). LTC₄ is metabolized to LTD₄, LTE₄, and N-acetyl-LTE₄ (Fig. 1). Predominant cellular sources of LTC₄ are eosinophils, mast cells, macrophages, and monocytes (Weller et al., 1983; Lewis and Austen, 1984; Williams et al., 1984). The cysteinyl leukotrienes are potent smooth muscle constrictors involved in inflammatory and anaphylactic reactions, in the release of luteinizing hormone, and in cell proliferation (Lewis and Austen, 1984; Baud et al., 1985; Hammarstrom et al., 1985; Kragballe et al., 1985; Piper and Samhoun, 1987; Samuelsson et al., 1987). Their effects are mediated through well-defined receptors on the cell surface (Mong et al., 1988; Winkler et al., 1988). In human isolated bronchi and lung parenchyma LTE₄ is less potent than either LTC₄ or LTD₄ (Piper and Samhoun, 1987). Although 25-fold less active than LTD₄ in the guinea-pig pulmonary parenchymal strip (Lewis et al., 1981), N-acetyl-LTE₄ is still a potent constrictor of rat mesenteric vessels (Siren et al., 1988).